The five major herpes viruses (Herpes simplex-1 (HSV-1), Herpes simplex-2 (HSV-2), Varicella-Zoster virus (VZV), Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are responsible for a variety of serious human diseases. Several of these viruses have also been linked to human maligancies. Anti-viral agents can be based on selective inhibition of virus-induced enzymes in infected or transformed cells. Two potent anti-viral agents, phosphonoacetate (PAA) and phosphonoformate (PFA), strongly inhibit virus-specific DNA polymerase. The inhibitory mechanism is not clear, but is related to their structural similarity to pyrophosphoric acid. It is proposed to develop new fluorinated and other phosphonate derivatives that may be useful to study and treat viral infections. Three new classes of fluorinecontaining pyrophosphate analog will be synthesized: a) fluoromethanediphosphonates (F-MDP); b) fluorophosphonoacetates (F-PAA); c) fluoromethanephosphonophosphinates (F-MPP). Desoxyribonucleoside triphosphate (dNTP) analogs of these compounds will also be synthesized, as probes of DNA polymerase inhibition. Novel hybrid nucleotides that combine in one molecule known anti-viral nucleosides (e.g. DHPG, BVdU, and acyclovir) with potent pyrophosphate analogs (e.g. monofluoro-PAA) will be prepared to determine whether enhanced inhibition occurs. The results will be compared with inhibition effects obtained with both independent drugs used in combination. In addition, PAA, MDP, and MPP derivatives containing a diazo group on the bridging methylene carbon will be investigated as possible photoaffinity inactivators of HSV-specific DNA polymerase. The new analogs will be tested for a) inhibition of HSV, CMV, and EBV replication in cell culture; b) inhibition of PFA-and acyclovir-resistant variants of HSV-1; c) in vivo activity against HSV-1 and HSV-2 in mice. Acid-base parameters and divalent cation (Zn, Mn, Ca) complexation constants will be determined for the analogs. The results, together with data obtained on structure-activity relationships, will be used to elucidate the mechanism of DNA polymerase inhibition by PAA-like substances with reference to their selectivity against the virus-induced enzyme. The research should materially aid the continuing search for compounds that have clinical value in the treatment of herpes virus infections and related diseases.